The present invention relates to a direct palladium catalyzed, regioselective process for the preparation of a wide variety of unsymmetrical, multifunctional N-substituted benzimidazoles or azabenzimidazoles of the formula (I) starting from 2-halo-nitroarenes and N-substituted amides.
Benzimidazoles play an important role in drug discovery and can certainly be regarded as privileged structures in pharmaceutical research (D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893-930). The ability of this benzimidazole scaffold to mediate an interaction with a variety of biological targets, is well-documented by the multitude of reports on the observed biological activity, as well as by the fact that several benzimidazole- or azabenzimidazole-based compounds are in development or marketed as drugs and make this type of heterocycle a important element for a valuable pharmaceutically active ingredient. (W. Wienen, M. Entzeroth, J. C. A. Van Meel, J. Stangier, U. Busch, T. Ebner, J. Schmid, H. Lehmann, K. Matzek, J. Kempthorne-Rawson, V. Gladigau, N. H. Hauel, Cardiovascular Drug Rev. 2000, 18, 127-156; N. H. Hauel, H. Nar, H. Priepke, U. Ries, J-M. Stassen, W. Wienen, J. Med. Chem. 2002, 45, 1757-1766.)
Of course the use of benzimidazoles or azabenzimidazoles is not limited to the above-mentioned pharmaceutical application. For example it is well known that benzimidazoles or azabenzimidazoles can be useful in agricultural applications like for example as herbicides, fungicides, nematicidals, parasiticides, insecticides, acaricides and arthropodicides or as diagnostic agents, liquid crystals and as polymers. In several cases, the benzimidazole or azabenzimidazoles is unsymmetrical and selectively substituted at one of the nitrogen atoms of the imidazole moiety. In contrast to the great importance of this scaffold no general regioselective route to N-substituted benzimidazoles or azabenzimidazoles has been described yet. The few methods available so far are multi-step processes often requiring harsh reaction conditions and are restricted in the substrate range, have poor cost-effectiveness and are thus of limited use (P. N. Preston, in The Chemistry of Heterocyclic Compounds, Vol. 40 (Eds.: A. Weissberger, E. C. Taylor), John Wiley & Sons, New York, 1981. P. L. Beaulieu, B. Haché, E. von Moos, Synthesis 2003, 1683-1692. D. Yang, D. Fokas, J. Li, L. Yu, C. M. Baldino, Synthesis 2005, 47-56; Y. M. Yutilov, Adv. Heterocycl. Chem. 2005, 89, 159-270). Furthermore, it is surprising that palladium-catalyzed reactions have hardly been used for the regioselective construction of an N-substituted benzimidazole scaffold and if so, the mentioned shortcomings were not eliminated (Katritzky, A. R.; Rachwal, S.; Ollmann, R.; J Heterocycl. Chem. 1994, 31, 775-779). Although palladium-catalyzed protocols for the cross-coupling between aryl halides and amides have been reported, very few examples employing 2-halo-nitroarenes exist. J. Yin, S. L. Buchwald describe in one example the coupling of 2-bromo-1-methyl-3-nitro-benzene with acetamide (Org. Lett. 2000, 2, 1101-1104) and R. G. Browning, V. Badarinarayana, H. Mahmud, C. J. Lovely, describe in one example the coupling of 1-bromo-2-nitro-benzene and a pyrrolidin-2-one derivative in moderate yield (Tetrahedron 2004, 60, 359-365). However, no general applicability for the palladium-catalyzed cross-coupling of 2-halo-nitroarenes, in particular 2-chloro-nitroarenes, and N-substituted amides was shown, and in addition no use was made to for the regioselective synthesis of benzimidazoles or azabenzimidazoles.
The limited regioselective access to N-substituted benzimidazoles or azabenzimidazoles often prevents the optimization of a potential drug substance or substance with for example agricultural application and is accompanied by poor cost-effectiveness. Thus the present invention is useful in preparing intermediates or end products of biological active compounds in pharmaceutical and agricultural applications.